1.alpha.-Hydroxyvitamin D compounds, specifically 1.alpha.,25-dihydroxyvitamin D.sub.3 and 1.alpha.,25-dihydroxyvitamin D.sub.2, are known as important regulators of calcium homeostasis and of proper bone formation in animals and humans. These compounds and certain structural analogs (e.g. 1.alpha.-hydroxyvitamin D.sub.3, 1.alpha.,-hydroxyvitamin D.sub.2 and related compounds) therefore find, or have been proposed for, many important uses in both human and veterinary medicine. Such uses include the prophylaxis and/or treatment of calcium metabolism disorders, such as renal osteodystrophy, rickets, osteomalacia, osteoporosis, the milk fever condition in animals, etc.
As a consequence of the medical utility of 1.alpha.-hydroxyvitamin D compounds, a variety of methods for their preparation have been developed. Summaries of these known methods have been presented, for example by Yakhimovich, Russ. Chem. Rev. 49,371 (1980), and DeLuca et al. Topics in Current Chem. vol. 83, p. 1-65 (1979), and DeLuca & Schnoes, Ann. Rev. Biochem. 52, 411 (1983).
Several of these preparatory methods for 1.alpha.-hydroxyvitamin D compounds result in mixtures of 5,6-cis and trans isomers (i.e. 1.alpha.-hydroxyvitamin D and the corresponding 5,6-trans isomer). Although for some therapeutic or other applications such mixtures may be used directly, it is generally the 5,6-cis product that is desired especially for medicinal formulations. Hence all synthetic methods yielding such cis/trans mixtures usually require separation of the isomers which is difficult and very laborious, and markedly reduces the yield of pure product.
Relevant to the present invention is specifically the 1.alpha.-hydroxylation method via 3,5-cyclovitamin D intermediates, as described in U.S. Pat. Nos. 4,195,027 and 4,260,549. In this method the C-3-hydroxy group of a vitamin D compound is tosylated, and the tosylate is subjected to solvolysis to obtain a 3,5-cyclovitamin intermediate. This intermediate is then oxidized to the 1.alpha.-hydroxycyclovitamin compound and the latter is solvolyzed to obtain a mixture of the 5,6-cis and 5,6-trans-1.alpha.-hydroxyvitamin D compounds (usually as the 3-acetate derivatives). Whenever, for pharmaceutical use, the 5,6-cis compound is the desired product, the cis/trans mixture resulting from solvolysis must be separated.
Also relevant is the method of Salmond, U.S. Pat. No. 4,206,131, for the preparation of 1.alpha.-hydroxyvitamin D compounds. In this procedure, 1.alpha.-hydroxy-5,6-trans-vitamin D compounds are produced as intermediates, which are then isomerized to the desired 5,6-cis vitamins. Since known isomerization methods result in mixtures of cis and trans vitamin D compounds, separation of the desired cis-product from the mixture is again required. Similarly, the 1.alpha.-hydroxylation methods proposed in U.S. Pat. Nos. 4,202,829, 4,263,215, 4,265,822, and 4,338,250, which involve direct 1-hydroxylation of 5,6-trans-vitamin D compounds, followed by 5,6-double bond isomerization, require, if the pure cis product is desired, methods for the separation of the 5,6-cis compound from the cis/trans mixture.
Because of the very similar chromatographic properties of the cis and trans isomers, such separation, though feasible, on a small scale with efficient columns, is very difficult, laborious and expensive, especially on a preparative scale. This difficulty in separating cis and trans isomers is thus a major disadvantage of the above methods.